Depression is a chronic disease that affects people of every age. Of various antidepressants currently used, the most successful one is a selective serotonin reuptake inhibitor (hereinafter, also abbreviated to SSRI). SSRI has a serotonin reuptake inhibitory effect higher than dopamine and noradrenalin reuptake inhibitory effects. The first drug put on the market as SSRI was zimelidine. Examples of other SSRIs that have then be launched or are under development include fluoxetine, fluvoxamine, citalopram, sertraline and paroxetine.
Although such SSRIs are widely used as therapeutic drugs for depression, it has been pointed out that they still have some problems. Examples of typical problems include: even SSRI does not exert a sufficient therapeutic effect on refractory depression patients, who occupy approximately ⅓ of all depression patients; and a period as long as 3 to 8 weeks is required for SSRI to exhibit its sufficient antidepressant effect. Thus, SSRI is slow in exhibiting its antidepressant effect, whereas its adverse reaction can occur immediately. Specifically, there arises the problem of a vulnerable period during which patients experience only adverse reaction without obtaining the therapeutic effect of the drug. Therefore, treating physicians are often heavily burdened with persuasion to convince their patients to continue medication with the same drugs even during this period. Furthermore, patients who are at risk of committing suicide restore their initiatives before experiencing sufficient improvement in the depressive symptoms due to the slow onset of the antidepressant effect. Therefore, there occurs the risk of suicide, the need for frequent hospitalization, or the like. Thus, it has been desired to develop an antidepressant that quickly exhibits an antidepressant effect.
The reason why SSRI requires a period as long as several weeks for exhibiting its antidepressant effect has been considered as follows:
SSRI inhibits acute serotonin reuptake in serotonin turnover. This inhibitory effect occurs in the nerve endings of serotonergic neurons. As a result, serotonin-mediated neurotransmission is potentiated, resulting in the onset of an antidepressant effect. However, this inhibitory effect also occurs in serotonergic neuronal cells or dendrites present in the raphe nuclei. Thus, in the raphe nuclei, the inhibited spontaneous firing (negative feedback reaction) of the serotonergic neurons via serotonin 1A autoreceptors is unintentionally potentiated. As a result, at the initial stage after administration of SSRI, the whole neurotransmission in the serotonergic neurons is not potentiated as much as expected. On the other hand, serotonin 1A autoreceptors on the serotonergic neuronal cells or dendrites of the raphe nuclei are desensitized as medication with SSRI is continued for several weeks. Thus, the negative feedback reaction disappears. As a result, the enhanced activities of the serotonergic neurons and the inhibited serotonin uptake in the nerve endings function in collaboration to potentiate serotonin neurotransmission, resulting in the onset of a sufficient antidepressant effect.
Thus, combined use with a serotonin 1A receptor antagonist blocks serotonin 1A autoreceptors to terminate the negative feedback reaction of serotonin. Alternatively, combined use with a serotonin 1A receptor agonist aggressively stimulates serotonin 1A autoreceptors to shorten the period up to desensitization. As a result, the period up to the onset of the effect of SSRI can be shortened or its antidepressant effect can be enhanced. In fact, it has been reported that the combined use of SSRI with pindolol having high affinity for serotonin 1A receptors enhances the effect of the serotonin reuptake inhibitor in depression patients and shortens the period up to the onset of its effect (Non Patent Literature 1).
When patients take drugs, fewer numbers or types of the drugs are desirable. Thus, based on the findings described above, it is considered that a compound having both of a serotonin reuptake inhibitory effect and affinity for serotonin 1A receptors can serve, in itself without being used in combination with other drugs, as a novel antidepressant that has a strong antidepressant effect and requires a shortened period for exhibiting its effect. It has been desired to develop such a compound as a drug.
A benzylpiperidine derivative having a substituted benzyl group at 4-position and a substituted phenylethyl group at 1-position has previously been reported (see e.g., Patent Literature 1) as the compound having both of a serotonin reuptake inhibitory effect and affinity for serotonin 1A receptors. Specifically, the literature discloses a serotonin reuptake inhibitor comprising cyclic amine represented by a formula (A), etc., as an active ingredient:
wherein R0 represents a hydrogen atom, a halogen atom, an alkyl group, a substituted alkoxy group, or the like, and a plurality of R0 moieties exist independently; R3 represents a hydrogen atom or the like; n represents an integer of 2 or the like; m represents an integer of 2 or the like; R5 and R6 each independently represent a hydrogen atom or the like; and Z represents a substituted aryl group or the like. The literature further discloses that these serotonin reuptake inhibitors have a serotonin 1A antagonistic effect.
Meanwhile, a compound having a substituted benzyl group at 4-position of piperidine has been reported in a plurality of literatures. Examples thereof include a literature that discloses a cyclic amine derivative acting as a therapeutic drug for cerebral vascular disorder (see Patent Literature 2) and a literature that discloses 4-substituted piperidine acting as an NMDA receptor antagonist (see Patent Literature 3).
Furthermore, a compound having a substituted phenylethyl group at 1-position of piperidine has also been reported in several literatures. An indole derivative having a piperidine ring having a cyclic ketone structure as a substituent on a phenylethyl group has been reported as a 5-HT1A antagonist (see e.g., Patent Literature 4). These indole derivatives differ in skeleton from benzylpiperidine compounds having a substituted benzyl group at 4-position of piperidine. Moreover, these indole derivatives have not been reported to also have a serotonin reuptake inhibitory effect.
Any of these patent literatures neither specifically disclose nor suggest a benzylpiperidine compound that has, at 4-position of piperidine, a benzyl group having an oxygen atom at 3-position of the benzene ring moiety and further has, at 1-position of piperidine, a 2-(chroman-6-yl)ethyl group or a 2-(4H-chromen-6-yl)ethyl group substituted by a hydroxy group and/or an oxo group.
Moreover, most of antidepressants such as tricyclic antidepressants (TCAs) or SSRIs are known to have a strong inhibitory effect on CYP2D6, which is an enzyme involved in drug metabolism and is a human cytochrome P450 molecular species. On the other hand, it is also known that most of therapeutic agents for psychiatric disease that can be used in combination with TCA or SSRI in the treatment of depression or anxiety symptoms are metabolized by CYP2D6. Thus, in the combined use of these drugs, the metabolism of the drug is inhibited on the basis of the CYP2D6 inhibitory effect of the other drug to thereby increase the serum concentration of the former drug. As a result, severe adverse reaction may occur. Thus, an antidepressant having a weaker CYP2D6 inhibitory effect has a smaller drug interaction with the combined therapeutic drug for psychiatric disease, which is metabolized by CYP2D6. Thus, such an antidepressant can be expected to serve as a highly safe drug, and it has been desired to develop it.
Furthermore, CYP2D6 is known to greatly vary in its enzyme activity between individuals due to genetic polymorphisms. Drugs that are metabolized at high rates by CYP2D6 greatly differ in in-vivo drug concentration between individuals and are at high risk of having a much higher serum drug concentration in a poor metabolizer (PM) than in an extensive metabolizer (EM). Moreover, such drugs are also in danger of exhibiting a stronger drug interaction with drugs inhibiting CYP2D6 or drugs undergoing metabolism by CYP2D6. Thus, the lower contribution ratio of CYP2D6 in drug metabolism results in the smaller pharmacokinetic influence of CYP2D6 attributed to genetic polymorphisms. Thus, such a drug can be expected to serve as a highly safe drug, and it has also been desired to develop it.